Process for the manufacture of vitamin a-acetate



. Patented Dec. 6, 1949 PROCESS FOR THE or VITAMIN amcETATE Otto Islet,Waldemar Guex, ane-res rreeawen, Basel, Switzerland, assignors toHoffmann-La Roche Inc., Nutley, J ersey N. J a corporation of New NoDrawing. Application April '7, 1948, serlalN'o. I 19,636. In GreatBritain, May 6, 1947 6 Claims. (crate-.488 l The present inventionrelates to a process for the manufacture of vitamin iii-acetate.

It has been found, according to the present invention, that vitaminA-acetate may be obtained in good yield by a process comprisingcondensing,

by means of a Grignard-reaction, 4-(2,6',6'-trimethyl-cyclohexene-(l')-yl) -2- methyl butene- (2) -yne-(4), hydrolyzing and purifying the 1,6-

dihydroxy-3,7- dimethyl -9- trimethyl cyclohexenyl-nonadiene-(2,7)-yne-(4) obtained and then partially acetylating the same by gradualaddition of one molof acetyl ehlorine in basic solution at a temperatureunder (3., partially hydrogenating at the triple bond the acetylcompound by the action of one mol of hydrogen in -'ch'a'rfcoal catalyst,

the presence or "a palladi" fonto which duinoline has been adsorbedprior to 11815, purifying the I -acebOXy 3fl-fiifi1thy1-6-hy- "(233)formed, dissolving the same'in an erganic J base, and adding to thesolution an equimolecul'ar quantity of phosphorus o'xycmoiid'e andheating the mixture; preferably in the presence of an inert solvent,such as toluene. It for instance, advantageous to react upon thepurified l-acetheizenyl-nonatriene (2,4,7) in Dyridine solution withanequimolecular quantity of phosphorusoxychloride at 95 C. in thepresence of toluene.

The purification of the 1-acetoxy-j3,7-dimethylone mol ofacetyl-chloride in the course of 24 hours. The 1,6-dihydroxy3,7-dimethy1-9stri! methyl 'cyclohexenyl-nonadiene-(2,7) -yne-.(4),obtained by 'Grignard-reaction, may be urified by crystallizatien a.solution :of petroleum ether. B'y-tha methods described, vitaminA:-a.c.etat.e is "obtained, possessing the same biological a ctiv-. ityas vitamin A-acet'ateohtained from natural sources. The acetate obtainedby the present process maybe hydrolysed to yield free vitamin A. .The.produetof the :present process is char.-. acterised by causing amaximum .of absorption in the ultra-iviolet spectrum at 328 m and by thecolour reactions with antimony trichloride (maximum of absorption at 620my and at 530 m n).

The product 'of the present invention may be purified "by the samemethods as hi h concen-- trates of vitamin A and its derivatives fromnai ural sources (separation between solvents; chr0- 'matographicadsorption. -'carefu1 distillation and crystallisation). Like naturalvitamin A, the produotrshouldn-be protected from the deteriora singefiects of light, airand heat. it is advisable to add anti-oxidantswhich may be present slu sing the whole :course of the synthesis; tocophroi are particularly suitable as antiwsi ants, I

The vitaminAsaceta-te, as obtained by the pres+ ent process, shbws, thefull biological activity of vitamin A and the acetate thereof obtainedfrom natural sources; wAscompared with the free alco+ hol, the highlyactive 'viatmin. Asacetate has the advantage AOf greater stability. Thevitamin A-a'cetate is particularly stable, can be prepared easilyzand isobtainable in crystallised form.

Example A solution of -18 parts by weight of -1-hydro xy3-methyl-pentene- (-2) '-iyne-(i) in 5Q -parts by vole ume-oi-ether isadded, in th ur e o one hou toa vigorouslystirred boiling solution ofethyl magnesium bromide, prepared from 10 parts by weight of mag es m,.50 p r s b we ght o e hyl br m de and 1 Parts by lume of et r h mixtureis refluxed ior 3 hours on an oil-bath of where on 33 pa ts by wei h of-(2',6-, tr me y syclohexene-41) i -2- methykbutene- (m al-(1) in 50parts by volume \"-v 3 of ether are added in the course of one hourwhile cooling with ice, and the mixture is refluxed for 3 hours. Aftercooling down, the reaction solution is poured into a mixture of 40 partsby weight of ammonium chloride and 200 parts by weight of ice, whilestirring. The hydrolysed condensation product is taken up in ether,washed successively with per cent. sulphuric acid and water, dried andconcentrated. In order to separate by-products, the residue is dissolvedin 75 per cent. methanol, and the solution is extracted with petroleumether of boiling range 30-70 C. The light-yellow methanol solution isdiluted with water, and the 1,6-dihydroxy-3,7-dimethyl-Q-trimethyl-cyclohexenyl nonadiene- (2,7)-yne-(4) precipitatingthereby is taken up in petroleum ether and isolated therefrom. It is ayellow, only terminal absorption in an ultra-violet absorption spectrum.The yield-is'about 88% of the theoretical. A crystalline form, ofmeltingpoint 57" C., of the 1,o-dihyoroxy-3,7-dimethyl- 9 trimethylcyciohexenyl nonadiene (2,7) yne-(4) may be obtained from dissolving tnesame in petroleum ether of boiling range 30-60" C. and cool ng the sameto 1 part by weight of 1,6-dihydroi ry-3,7-di nethy1-'Q-trimetnyl-cyclonexeny -nonadiene- (2,7) yne'-- (4) is dissolved in 5parts by volume of pyridine and a parts by'volume-zoftpetroleum ether,and a solution of 0.249 part by weight of acetyl chloride in a parts byvolume of petroleum ether are added thereto in the course of 24 hours at2() C. The reaction solution is poured on a mixture of ice and water.The petroleum ether solution is washed successively with normalsulphuric acid. aqueous sodium bicarbonate solution and water, driedwith potassium carbonate and concentrated. 1.1 part by weight'ofsl-acetoxy-tifl-dimethyl G-hydroxy9-trlmethylcyclohexenylnonadiene-(2,7)-yne-(4) is'obtaincd as a yellowoil of n =l.518.

1 part by weight of this partially acetylated compound is dissolved in 5parts by volume of methyl alcohol, whereupon one moi-oi hydrogen isadded thereto at room temperature in the pres.- ence of 0.1 part byweight of 4 percent-palladium charcoal, onto which quinoline has beenadsorbed prior to use. Hydrogenation-is then discontinued, the catalystis filtered off, the filtrate is diluted with water and the reactionproduct is extracted with petroleum ether. Dihydroxy compounds areremoved from the petroleum ether solution by extraction with diluteaqueous methanol. Thereafter,1-acetoxy-3,7-dimethyl-6-hydroxy-9-trimethylcyclohexenyl-nonatriene-(2,4,7)is extracted with 95 per cent. methanol and isolated therefrom in theusual manner. The substance is a viscous oil of n =l.5140; d4 =0.9965.

1 part by weight of 1-acetoxy-3,7-dimethyl-6- hydroxy-9-trimethylcyclohexenyl nonatriene- (2,4,7) in 3 parts by volume of toluene isadded, at a bath-temperature of 95 C., to a solution of 0.33 part byvolume of phophorus-oxychloride in 2 parts by volume of pyridine and 4parts by volume of toluene. The mixture-is stirred for 30 minutes, thendiluted with petroleum ether, poured on ice, and the petroleum ethersolution is washed successively with normal sulphuric acid, sodiumbicarbonate solution and 92 per cent. methanol and water and dried withsodium sulphate, whereupon the solvent is evaporated. The crude productthus obtained, a red-brown oil of n =about 1.560, may be purified bychromatothe Yellow 011 by very viscous oil of n =L535 showing 7 graphicabsorption (for instance, percolation chromatogram onto an aluminumoxide column) and by crystallisation (for instance, from a mixture ofacetone and fine spirit).

The course of the reaction described in the instant application may begraphically illustrated by the following chart in which the symbol Itrepresents the following portion of the molecule:

v RCH=CH-C=CHCH?CHC=OH-CH;O0CCH5 HI a We claim: 1. Process whichcomprises partially acetylating 1,6-dihydroxy-3,7- dimethyl9-[2',6',6'-tri nieth'yl-cyclohexene-(l') 311] nonadiene (2,7) l yne-4with a'cetyl-chloride in basic solution at "a temperature below 0 C. toform the correspond ing l-acetoxy-G-hydroxy compound, hydrogenating saidacetoxy compound to form 1-acetoxy-3,7- dimethyl-6-hydroxy-9-[2,6',6-trimethyl cyclo' hexene-(l')-yl]-nonatriene-(2,4,7) and there'-after reacting said nonatriene'with phosphorous oxychloride to producevitamin A acetate. 2. Process which comprises reacting l-acetoxy-3,7-dimethyl-6-hydroxy-9-[2,6',6-trimethy1-cy clohexene- (1') -yl]-nonatriene- (2,4,7) with phosphorus oxychloride to form vitaminAacetate. 3. Process which comprises reacting l-acetoxy;3,7-dimethyl-6-hydroxy-9-[2',6,6-trimethyl-cy clohexene- (1 -yll-nonatriene- (2,4,7) with phos phorus oxychloride to form vitamin Aacetate, the reaction being carried out in the presence of an organicbase. i 4. Process which comprises reacting l-acetoxy-3,7-dimethyl-6-hydroxy-9-[2',6',6'-trin'lethyl-cy clohexene-(l)-yl]-nonatriene-(2,4,'l) with phosphorous oxychloride to form vitamin Aacetate, the reaction being carried out in the presence of toluene andpyridine.

5. Process which comprises reacting l-acetoxy-3,7-dimethyl-8-hydroxy-9-[2',6',6'-trimethyl-cyphorous oxychloride toform vitamin A acetate.

9. temperature of 95 C. being employed in the reaction.

OTTO ISLER. WALDEMAR GUEX. PETER mmnwm 6 REFERENCES CITED The followingreferences are of record in the fiie of this patent:

5 UNITED STATES PATENTS Number I Name I Date 2,369,157 mlas Feb. 13,1945 2,359,159 Milas Feb. 13, 1945 lo 2,4i2,465 Milas Dec. 10, 1946OTHER REFERENCES Isler et ai., Helv. Chim. Acta. 30, 1911-1927 1947).

Certificate of Correction Patent No. 2,490,358 December 6, 1949 o'r'roISLER ET AL.

It is hereby certified that errors appear in the printed specificationof the above numbered patent requiring correction as follows:

Column 1, line 13, for the word chlorine read chloride; column 4,line24, for that portion of the formula reading CO read CH and that thesaid Letters Patent should be read-with these corrections therein thatthe same may conform to the record of the case in the Patent Ofiice.

Signed and sealed-this 28th day of March, A. D. 1950.

THOMAS F. MURPHY,

Assistant Uownmissz'mir of Patents.

